One of the most serious and least understood risk factors for tuberculosis (TB) is diabetes mellitus (DM), a disease complex that is reaching epidemic proportions in many parts of the world. Because there have been few studies conducted to better understand the complex interactions between TB and DM, very little is known about the basic disease pathogenesis. Based on the limited number of epidemiological and clinical studies in humans, we know that patients with DM have poorer clinical outcomes and are at greater risk of dying compared to non-diabetic patients with TB. TB and DM share a common pathogenesis related to excessive oxidative tissue damage. Central to our proposal is the use of experimental Mycobacterium tuberculosis (Mtb) infections in guinea pigs (GPs), which develop pulmonary and extra-pulmonary lesions similar to humans with naturally occurring TB. In the proposed research we hypothesize that depletion of antioxidant capacity leads to oxidative tissue damage, that this basic disease mechanism is shared by both diseases, and, when combined, lead to more severe and widely disseminated TB with a poor response to conventional antimicrobial therapy. We will test this hypothesis with novel models of insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type 2) concurrent with infection by the highly virulent Erdman KO1 stain of Mtb. We will use these models to explore basic disease pathogenesis and to test novel therapeutic strategies that can be used to treat humans. Our preliminary data show that Mtb-infected GPs with elevated blood glucose levels developed more severe and widely disseminated TB lesions with a higher bacterial burden compared on GPs with normal blood glucose levels. In addition we show that Mtb infection alone induces a state of chronic hyperglycemia and that this condition may exacerbate disease and limit response to therapy. Our aims are to: (1) validate the models of TB combined with IDDM and NIDDM in GPs, (2) define the role of oxidative stress and the depletion of antioxidant defenses in the pathogenesis of TB in GPs with DM, (3) determine whether antioxidant drugs can restore antioxidant defenses, and (4) whether they will enhance the effectiveness of anti- TB drugs in GPs with IDDM and NIDDM. By better understanding the pathogenesis of TB concurrent with DM, new treatment strategies can be added to the global fight to control human tuberculosis especially in patients with these known risk factors. PUBLIC HEALTH RELEVANCE: Humans with diabetes are at higher risk of developing severe tuberculosis (TB) compared to non- diabetics. For unknown reasons, both diabetes and TB are difficult to treat when they occur together. The goal of our research is to develop a model of TB in guinea pigs with diabetes that can be used to test new treatment strategies for both diseases. What we learn from treating diabetic guinea pigs with TB can be directly applied to the human disease combination, a problem which is now emerging around the world.